Novel process for the etherification of bis-resorcinyol triazines

ABSTRACT

The invention relates to an improved process for the manufacture of bis-resorcinyl triazines of formula (I), wherein R 1  is hydrogen, a C 1 -C 18 alkyl group or a C 2 -C 18 alkenyl group and R 2  is a C 1 -C 18 alkyl group or a C 2 -C 18 alkenyl group. (I)

The invention relates to an improved process for the manufacture ofbis-resorcinyl triazines of formula (I), wherein R¹ is hydrogen, aC₁-C₁₈alkyl group or a C₂-C₁₈alkenyl group and R² is a C₁-C₁₈alkyl groupor a C₂-C₁₈alkenyl group.

Bis-resorcinyl triazines of formula (I) such as for example Tinosorb S[INCI Name: Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine] are highlyeffective UV-absorbers which may, for example, be used as lightscreening agents in cosmetic products.

The preparation of bis-resorcinyl triazines of formula (I) is known ande.g. disclosed in U.S. Pat. No. 5,955,060. The preparation encompassesthe reaction of cyanuric chloride with a phenyl magnesium bromidecompound in a Grignard reaction to a dichlorotriazine. The tworesorcinyl groups are then introduced by a Friedel-Crafts acylation withresorcinol in the presence of a Lewis acid, in particular an aluminiumhalide. In a third step, the etherification of the free 4-hydroxylgroups of the resorcinyl residues is carried out by alkylation in thepresence of a base. The disclosed alkylation processes of the examples,however, are not satisfactory in view of reaction times, selectivity andyields. Furthermore, the processes involve chromatography techniques toisolate the products, which are tedious, labor intensive and timeconsuming and thus not suitable for industrial scale as this result inunacceptable manufacturing cost.

Thus, there is a need in the art to develop a simple, industriallyfeasible and scalable process for the synthesis of bis-resorcinyltriazines of formula (I) that would avoid the aforementioneddifficulties.

The present inventors have found an improved process for the preparationof bis-resorcinyl triazines of formula (I) involving specific bases andreaction conditions, which is useful for scale up and results in highyields and purities.

Thus in a first aspect the present invention relates to a process (A)for the preparation of bis-resorcinyl triazines of formula (I),

wherein R¹ is hydrogen, a C₁-C₁₈alkyl group or a C₂-C₁₈ alkenyl group,and

-   -   R² is a C₁-C₁₈alkyl group or C₂-C₁₈ alkenyl group,        said process comprising the step of reacting a bis-resorcinyl        triazine of formula (II) in dimethylformamide with an alkyl        halide R²—X, wherein X is Cl, Br or I, in the presence of a        base, characterized in that the base is selected from the group        consisting of sodium carbonate, sodium phosphate and sodium        hydrogencarbonate and the reaction temperature is selected in        the range of at least 120° C. (at atmospheric pressure).

It is well understood that the reaction temperature would have to beadjusted accordingly if pressure/vacuum would be applied to the processof the present invention, which temperature, however, could easily beadjusted by a person skilled in the art and which embodiment isincorporated herein as well.

Dimethylformamide [CAS 68-12-2] is also known as N,N-Dimethylformamide.

Examples of C₁-C₁₈alkyl groups or C₂-C₁₈alkenyl groups are branched orunbranched alkyl, respectively alkenyl groups such as methyl, ethyl,n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,n-heptyl, 2-ethylhexyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,prenyl, 2-propenyl and 3-butenyl groups.

In all embodiments of the present invention R¹ is preferably aC₁-C₅alkyl group, more preferably a C₁-C₂alkyl group, most preferably amethyl group.

In all embodiments of the present invention R² is preferably aC₃-C₁₀alkyl group, more preferably a C₆-C₁₀alkyl group and mostpreferably an ethylhexyl group.

In all embodiments of the present invention most preferably R¹ is amethyl group and R² is an ethylhexyl group.

Suitable alkyl halides encompass in particular the respective bromidesor chlorides, the chlorides being preferred. Most preferably ethylhexylchloride [CAS 123-04-6] is used in the processes according to thepresent invention.

Thus in a particular advantageous embodiment, the invention encompassesa process (B), which is a process (A), wherein R¹ is a methyl group, R²is an ethylhexyl group and the alkyl halide R²—X is ethylhexyl chloride.

Sodium carbonate [CAS 497-19-8], sodium phosphate [CAS 7601-54-9] andsodium hydrogen carbonate [144-55-8] are well known to a person skilledin the art and can e.g. be purchased at Sigma-Aldrich. In allembodiments of the present invention, preferably anhydrous sodiumcarbonate or anhydrous sodium hydrogen carbonate, most preferablyanhydrous sodium carbonate is used. Most preferably anhydrous sodiumcarbonate with a purity 99%, such as preferably with a purity of 99.5%,most preferably with a purity of 99.9% (assay, calculated based on drysubstance) is used in the processes according to the present invention.

Thus, in another advantageous embodiment, the invention encompasses aprocess (C), which is a process (B), wherein the base is anhydroussodium carbonate, preferably anhydrous sodium carbonate with a purity of≥99%, such as preferably with a purity of ≥99.5%, most preferably with apurity of ≥99.9% (assay, calculated based on dry substance).

In all embodiments of the present invention, the reaction temperature(at atmospheric pressure, i.e. 1013 mbar) is preferably selected in therange of 120-155° C., more preferable in the range of 130-155° C., andmost preferably in the range of 130-145° C. In a very advantageousembodiment the reaction temperature is selected such that the reactionis maintained at reflux (i.e. a reaction temperature of about 133-143°C., at atmospheric pressure), which can easily be adjusted by a personskilled in the art. If desired the reaction could also be performedunder reduced or increased pressure, while the temperature is adjustedaccordingly, which is well known by a person skilled in the art.Preferably the reaction is, however, in all embodiments of the presentinvention carried out at atmospheric pressure.

Thus, in a further advantageous embodiment, the invention encompasses aprocess (D), which is a process (C), wherein the temperature is selectedsuch that the reaction is maintained at reflux (i.e. at about 133-143°C., at atmospheric pressure).

The reaction time in all processes according to the present invention isgenerally adjusted such that all of the compound of formula (II) isconsumed and the amount of mono-alkylated product (i.e. one of R² isstill hydrogen) is <8%, preferably <5%, more preferably <4% (traced byHPLC: area %, detection at 230 nm). Advantageously, the reaction time isselected in the range of 3 to 24 h, preferably in the range of 4 to 20h, most preferably in the range of 5-15 h.

The molar ratio of the base to the compound of formula (II) ispreferably selected in the range of 2 to 9, most preferably in the rangeof 3 to 7.

Thus, in an additional advantageous embodiment, the inventionencompasses a process (E), which is a process (D), wherein the molarratio of the base to the compound of formula (II) is selected in therange of 3 to 7.

In all embodiments of the present invention, the amount ofdimethylformamide is preferably selected such that the amount of thecompound of formula (II) in dimethylformamide is in the range of 0.5 to2 mol/l, preferably in the range of 0.75 to 1.5 mol/l, most preferablyin the range of 0.8 to 1 mol/l.

In all embodiments of the present invention, the alkyl halide R²—X ispreferably used in a slight excess. Preferably, the amount of the alkylhalide R²—X is selected in the range of 1.5 to 6 mol-equivalents,preferably in the range of 2 to 5 mol-equivalents, more preferably inthe range of 2.5 to 4 mol-equivalents, most preferably in the range of 3to 3.5 mol-equivalents relative to the compound of formula (II).

Thus, in an additional advantageous embodiment, the inventionencompasses a process (F), which is a process (E), wherein the amount ofdimethylformamide is selected such that the amount of the compound offormula (II) in dimethylformamide is in the range of 0.8 to 1 mol/1 andthe amount of ethylhexyl chloride is selected in the range of 3 to 4mol-equivalents relative to the compound of formula (II).

Preferably, the base is added in two portions, the first portion beingused to neutralize the solution of the compound of formula (II) indimethylformamide to about pH 6.5 to 7.5, preferably to about pH 7.Generally about 15-30 wt.-% based on the total amount of the base is tobe used for the neutralization step, the amount being easily adjustableby a person skilled in the art.

Thus, in a particular advantageous embodiment the process according tothe present invention encompasses the following consecutive steps,wherein all the definitions and preferences as given above also apply:

-   (i) suspending the compound of formula (II) in dimethylformamide-   (ii) heating the resulting suspension to 90-155° C., preferably to    95-145° C., until a solution is formed,-   (iii) neutralization of the resulting solution to about pH 7 with    the first portion of the base,-   (iv) addition of the second portion of the base, followed by the    addition of the alkyl halide R²—X-   (v) heating of the resulting mixture to reflux.

Advantageously, the reaction time in step (v) is selected in the rangeof 3 to 24 h, preferably in the range of 4 to 20 h, most preferably inthe range of 5-15 h.

In a further advantageous embodiment, the process encompasses thefurther steps of

-   (vi) filtration of the resulting reaction mixture obtained in    step (v) followed by-   (vii) addition of 2-butanol and crystallization of the compound of    formula (I) from the dimethylformamide/2-butanol mixture.

The amount of 2-butanol can easily be determined by a person skilled inthe art and is preferably selected in the range of 0.5 to 5 l/mol ofcompound of formula (II), such as preferably in the range of 2 to 4 Vmol of compound of formula (II).

Each reaction of the process according to the invention can in principlebe carried out in any reactor suitable for the respective reaction type.Without restricting generality, the following are mentioned by way ofexample: suspension reactor, stirred tank, stirred tank cascade, tubularreactor, shell-type reactor, shell and tube reactor, fixed-bed reactor,fluidized-bed reactor, reactive distillation column.

Experimental Part2,4-Bis{[4-(2-ethylhexyloxy)-2-hydroxy]phenyl}-6-(4-methoxyphenyl)-1,3,5-triazine

In a 100 ml sulfonation flask equipped with a stirrer, dropping funnel,condenser and internal thermometer, 15 g (31.3 mmol, 84% purity) of2,4-bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine (IIa)are introduced together with 35 ml dimethylformamide [and the resultingsuspension was heated to 100° C. upon which a clear solution was formed.Then the resulting solution was neutralized with a first portion of therespective base to pH 7. Afterwards, the second portion of the base inthe amount as indicated in table 1 was added, followed by the additionof ethylhexyl chloride (EH-CI, mol-equivalent relative to (IIa)). Thenthe reaction was heated to reflux (about 133-143° C.), except whereindicated otherwise in table 1, until the starting material (IIa) wasfully consumed and the amount of the respective mono-alkylated productwas <8% (HPLC, detection at 230 nm, relative area % to (Ia) in thereaction mixture). The reaction was then cooled to 80° C. and filtered.The obtained solution was diluted with 90 ml of 2-butanol, cooled to 20°C. and seeded with 2-3 crystals of2,4-Bis{[4-(2-ethylhexyloxy)-2-hydroxy]phenyl}-6-(4-methoxyphenyl)-1,3,5-triazine(Ia). After complete crystallization (about 3.5 h) the crystals wereisolated by filtration resulting in2,4-Bis{[4-(2-ethylhexyloxy)-2-hydroxy]phenyl}-6-(4-methoxyphenyl)-1,3,5-triazinein the yields and with the purity as illustrated in table 1.

TABLE 1 Base EH-Cl (mol-eq. (mol-eq. Pu- Exam- relative relative tYield¹ rity² ple to (IIa)) to (IIa)) [hours] [%] [%] 1 Ref K₂CO₃ (3.2)3.2 4.5 h 62 95.4 (T = 130° C.) 2 Ref K₂CO₃ (3.2) 3.2 5 h 59 96.7 (T =130° C.) 3 Ref Na₂CO₃ (2.8) 2.8 48 h 53 97.5 (T = 105° C.) 4 Ref K₂CO₃(2.8) 2.8 48 h 61 96.2 (T = 105° C.) 5 Ref NaOH 50% 2.4 95 h  31³ n.a.aq. (2.4) (T = 105° C.) 6 Ref K₂CO₃ (3.5) 3.5 3.5 h 36 96.5 1 Na₂CO₃(3.5) 3.5 7 h 85 96.6 2 Na₂CO₃ (3.5) 3.5 7 h 87 96.8 3 NaHCO₃ (3.5) 3.58 h 75 96.0 4 NaHCO₃ (3.5) 3.5 11 h 78 97.1 5 Na₃PO₄ (3.5) 3.5 10.5 h 6596.3 ¹corrected for purity ²based on quantitative HPLC ³yield based onHPLC area % after 95 h

Furthermore, the procedure described in example 1c of U.S. Pat. No.5,955,060 was followed, resulting, however, in no detectabledi-alkylated product even after 90 h. Only mono-alkylated product wasdetected.

1. Process for the preparation of bis-resorcinyl triazines of formula(I),

wherein R¹ is hydrogen, a C₁-C₁₈alkyl group or a C₂-C₁₈ alkenyl group,and R² is a C₁-C₁₈alkyl group or C₂-C₁₈ alkenyl group, said processcomprising the step of reacting a bis-resorcinyl triazine of formula(II)

in dimethylformamide with an alkyl halide R²—X, wherein X is Cl, Br orI, in the presence of a base, characterized in that the base is selectedfrom the group consisting of sodium carbonate, sodium phosphate andsodium hydrogencarbonate and the reaction temperature is selected in therange of at least 120° C. (at atmospheric pressure).
 2. The processaccording to claim 1, wherein R¹ is a C₁-C₅alkyl group, preferably aC₁-C₂alkyl group, most preferably a methyl group.
 3. The processaccording to claim 1, wherein R² is a C₃-C₁₀alkyl group, preferably aC₆-C₁₀alkyl group, most preferably an ethylhexyl group.
 4. The processaccording to claim 1, wherein R¹ is a methyl group and R² is anethylhexyl group.
 5. The process according to claim 1, wherein the alkylhalide R²—X is an alkyl chloride with X being Cl.
 6. The processaccording to claim 1, wherein the alkyl halide R²—X is ethylhexylchloride.
 7. The process according to claim 1, wherein the base isanhydrous sodium carbonate.
 8. The process according to claim 1, whereinthe reaction temperature is selected in the range of 120-155° C. (atatmospheric pressure).
 9. The process according to claim 1, wherein thereaction temperature is selected such that the reaction is maintained atreflux.
 10. The process according to claim 1, wherein the molar ratio ofbase to the compound of formula (II) is in the range of 2 to 9,preferably in the range of 3 to
 7. 11. The process according to claim 1,wherein the amount of dimethylformamide is selected such that the amountof the compound of formula (II) in dimethylformamide is in the range of0.5 to 2 mol/1, preferably in the range of 0.75 to 1.5 mol/1, mostpreferably in the range of 0.8 to 1 mol/1.
 12. The process according toclaim 1, wherein the amount of the alkyl halide R²—X is selected in therange of 1.5 to 6 mol-equivalents, preferably in the range of 2 to 5 molequivalents, most preferably in the range of 2.5 to 4 mol-equivalentsrelative to the compound of formula (II).
 13. The process according toclaim 1, wherein the process encompasses the following consecutive stepsof (i) suspending the compound of formula (II) in dimethylformamide (ii)heating the resulting suspension to 90-155° C. (at atmosphericpressure), preferably to 95-145° C., until a solution is formed, (iii)neutralization of the resulting solution to pH 7 with the first portionof the base, (iv) addition of the second portion of the base, followedby the addition of the alkyl halide R²—X (v) heating of the resultingmixture to reflux
 14. The process according to claim 13, wherein thereaction time in step (v) is selected in the range of 3 to 24 h,preferably in the range of 4 to 20 h, most preferably in the range of5-15 h.
 15. The process according to claim 13, wherein the processfurther comprises the steps (vi) filtration of the resulting reactionmixture obtained in step (v) followed by (vii) addition of 2-butanol andcrystallization of the compound of formula (I) from thedimethylformamide/2-butanol mixture.